Natural and synthetic retinoid compounds have been used to treat a variety of hyperproliferative skin disorders as well as other skin disorders including, for example, acne, psoriasis, wrinkling, sun-damaged skin, and age spots. (See Fox L P et al., Goodman & Gilman's: The Pharmacological Basis of Therapeutics, Section XIII-Dermatology, 11th Ed.) In many cases, retinoids have been applied topically. Retinoic acid has also been administered orally to treat severe cases of acne. For example, Accutane® contains 13-cis-retinoic acid, also referred to as isotretinoin, which is related to both retinoic acid and retinol, i.e., vitamin A. (See Remington, The Science and Practice of Pharmacy p. 1288-1289, 21st Ed.). Accutane® has been approved for treating nodular acne by administering oral pharmacologic dosages of 0.5 to 2.0 mg/kg/day which inhibits sebaceous gland function and keratinization.
Retinoids are natural and synthetic compounds that are structurally related to vitamin A. All-trans retinol is the major circulating form of vitamin A. It is oxidized in the body: first to all-trans retinaldehyde, and then to all-trans retinoic acid (atRA). (Blomhoff et al., 1992, Annu. Rev. Nutr. 12:37-57; and, Moise et al., 2007, Biochemistry 46:4449-4458). atRA is the functional form of the vitamin that regulates growth, cellular differentiation, and embryonic development, whereas all-trans retinaldehyde functions in the visual cycle. (Clagett-Dame et al., 2002, Annu. Rev. Nutr. 22:347-381). Because atRA is such a potent regulatory molecule, it is formed in very small amounts, and it is rapidly metabolized such that its half-life is relatively short. (Roberts et al., 1967, Biochem. J. 102:600-605).
Systemic administration of retinoids has also been indicated for diseases such as pityriasis, rubra pilaris, condylomata accuminata, skin cancers, rosacea, hidradenitis, suppurativa, granuloma annular, lupus erythematosus and lichen planus. (Akyol M et al., 2006, Am. J. Clin. Derm. 6(3), 175-184).
Topical administration of retinoids has been limited largely due to side effects such as skin irritation (e.g., redness and burning), dryness and photosensitivity reactions. (Akhavan et al., 2003, Am. J. Clin. Dermatol. 4:473-492). Oral administration of retinoids has been even more limited due to more serious side effects such as teratogenicity (e.g., fetal malformation), elevation of triglyceride, cholesterol, and transaminase levels, bone demineralization, and other side effects associated with topical administration (e.g., drying of mucosal membranes and photosensitivity). (Armstrong et al., 1994, The Retinoids, pp. 545-572; and, DiGiovanna, 2001, J. Am. Acad. Dermatol. 45:S176-S182). Such numerous and varied sided effects have substantially limited the medical and pharmaceutical use of retinoids, particularly those related to skin therapies.
It is believed that retinoic acid and other synthetic retinoids bind to and regulate the transcriptional activity of a family of nuclear proteins known as the retinoic acid receptors (“RARs”). (Chambon, 1996, FASEB J. 10:940-954; Clagett-Dame et al., 1997, Crit. Rev. Euk. Gene Exp. 7:299-342; and, Mark et al., 2006, Annu. Rev. Pharmacol. Toxicol. 46:451-480). All-trans-retinoic acid is the endogenous ligand for the RAR family of receptors. The 13-cis retinoic acid isomer does not bind to the RARs. (Repa J J et al., 1993, Proc. Natl. Acad. Sci. USA 90:7293-7297). The 13-cis retinoic acid isomer must isomerize to all-trans-retinoic acid that is active in terms of receptor binding and activation.
It has been reported that the active hormonal form of vitamin D (i.e., calcitriol) and various synthetic analogs thereof demonstrate differentiative, antiproliferative and immunomodulatory activity. Such compounds have also demonstrated therapeutic efficacy in treating skin disease such as psoriasis. (See Smith E L et al, 1988, J. Am. Acad. Dermatol., 19, 516-528; and Holick, M F, 1989, Arch. Dermatol., 125, 1692-1697). It is also been reported that calcitriol and therapeutic analogs thereof are used to target the nuclear vitamin D receptor. (DeLuca H F, 2004, Am. J. Clin. Nutr. (Suppl) 1689S-1696S). It is believed that calcitriol and therapeutic analogs thereof may act directly within the epidermis on basal keratinocytes and Langerhans cells as well as on other cells within the immune system. The use of calcitriol and various synthetic analogs at therapeutic dosages is further limited by side effects such as hypercalcemia, hypercalcuria and calcification of soft tissues.
Recently, a new class of vitamin D analogs, referred to as 19-nor vitamin D compounds, has been discovered. 19-Nor vitamin D compounds are characterized by replacement of the A-ring exocyclic methylene group at the 19 carbon (in typical vitamin D molecules) with two hydrogens. Further substitution at the 2-position and/or modification of the side chain at 17 carbon of the five-membered ring has yielded pharmacologically active compounds that are much less calcemic at physiologically active concentrations as compared to the native hormone. (Plum, L. A. et al., Proc. Natl. Acad. Sci. USA, 101(18), 6900-9004 (2004)). Some 19-nor-containing vitamin D analogs have also exhibited enhanced potency and tissue selectivity activities suggesting that such analogs may have important therapeutic advantages over the native vitamin D hormone or other less-selective and/or non-selective analogs. (See Sicinski R R et al., 1998, J. Med. Chem., 41, 4662-4674; and, Shevde N K et al., 2002, Proc. Natl. Acad. Sci. USA, 99(21), 13487-13491).
Acne is a condition of the pilosebaceous unit. Acne involves a spectrum of effects including non-inflammatory comedones, inflammatory papules, pustules and cysts. When administered topically or systemically, retinoids cause epidermal hyperproliferation leading to comedolysis and improvement of the disease. (See Fisher G J et al., 1996, Molecular Mechanisms of Retinoid Actions in the Skin, FASEB. J 10:1002:21013). Although very effective, retinoid therapy is substantially limited by the number and extent of side effects, which are particularly limiting when retinoids are administered orally. (See Fox L P et al., 2006). Thus, there is an important and substantial need for retinoid-containing therapies having reduced side effects to treat various skin disorders such as acne.